Modulation of Advanced Glycation End Products by Candesartan in Patients with Diabetic Kidney Disease-A Dose-Response Relationship Study
Saha, Sandeep A MD; LaSalle, Brian K BSN; Clifton, G Dennis PharmD; Short, Robert A PhD; Tuttle, Katherine R MD, FACP, FASN American Journal of Therapeutics (In press)
Advanced glycation end products (AGEs) are proinflammatory mediators implicated in the pathogenesis of diabetic kidney disease (DKD). In this study, dose-dependent effects of angiotensin receptor blockade on urinary AGEs were evaluated in patients with DKD. Patients with type 2 diabetes and proteinuria >=500 mg/d (n = 11) were compared with diabetic controls without DKD (n = 10) and normal controls (n = 11). After a 2-week washout period, DKD participants were treated with candesartan doses progressively increasing from 8, 16, 32, to 64 mg/d every 3 weeks for a total of 12 weeks. Other antihypertensive agents were adjusted to maintain stable blood pressure. At baseline and after each dosing period, blood pressure measurements and 24-hour urine collections were obtained. Urinary carboxymethyl lysine, an AGE biomarker, was reduced over the 12-week dose escalation protocol (r = 0.38, P = 0.01) in DKD participants. Creatinine clearance increased slightly, but albuminuria was unaffected by candesartan administration. Baseline urinary transforming growth factor-[beta]1 excretion was lower in DKD participants than in controls and did not change during the study period. Reducing kidney exposure to AGEs may be a mechanism of protection by angiotensin receptor blockade in DKD. AGEs may also impact the diabetic kidney through mechanisms independent of transforming growth factor-[beta]1. (Abstract on line)

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